The present invention relates to conjugates of camptothecin and analogs thereof and taxoid groups, pharmaceutical formulations containing the same, and methods of use thereof as antimitotic and antitumor agents, particularly for the treatment of cancers such as breast cancer, ovarian cancer and prostate cancer.
Paclitaxel (1) as shown in FIG. 1 and camptothecin (2) also shown in FIG. 1 are both plant-derived antitumor agents currently in clinical use (M. C. Wani et al., Taxus brevifolia, 1971, 93, 2325-2327 and M. E. Wall et al., J. Am. Chem. Soc., 1966, 88, 3888-3890). Paclitaxel was approved by the FDA for treatment of advanced ovarian cancer in 1992 and for treatment of breast cancer in 1994.
The mechanism of the antitumor effect of paclitaxel is antimitotic, specifically promoting the irreversible assembly of tubulin into microtubules (P. B. Schiff et al., Nature, 1979, 277, 665-667). Camptothecin also posseses significant antitumor activity which is attributable to inhibition of DNA topoisomerase I (DNA topo I) (Y. H. Hsiang et al., J. Biol. Chem., 1985, 260, 14873-14878 and J. C. Wang, Biochim. Biophys. Acta., 1987, 909, 1-9). Both compounds have been subject to continual structural modification aimed at developing more useful chemotherapeutic agents. However, although both paclitaxel and camptothecin possess potent antitumor activity, recent reports have shown that treatment with these drugs often results in a number of undesired side effects as well as multi-drug resistance. Therefore, it remains essential to develop new anticancer agents with fewer side effects and improved activity against various classes of tumors.
Previously we reported synthesis and evaluation of two 4xe2x80x2-O-demethyl epipodophyllotoxin-camptothecin conjugates (3 and 4 as shown in FIG. 1) as inhibitors of mammalian DNA topoisomerases I and II (K. F. Bastow et al., Bioorg. Med. Chem., 1997, 5, 1481-1488). The most active conjugate inhibited cell growth similarly to both topo I- and II-inhibitory components. These conjugates were more cytotoxic than epipodophyllotoxin in several cancer cell lines including HOP-62 leukemia, SW-620 colon cancer, MCF/ADR adriamycin-resistant breast cancer and A-498 renal cancer. One conjugate was more active than either etoposide or (2) against human KB (nasopharnyx) and DU-145 (prostate) tumor cell growth in nude mice. Currently, there are several reports describing conjugates between paclitaxel and either daunorubicin or chlorambucil (A. K. Kar et al., Bioorg. Med. Chem. Let., 2000, 10, 261-264 and M. D. Wittman et al., Bioorg. Med. Chem. Let., 2001, 11, 811-814). However, DNA topisomerase inhibitor-paclitaxel hybrids have not been investigated.
According to embodiments of the present invention, the present invention relates to a compound according to formula I:
Cxe2x80x2xe2x80x94Lxe2x80x94Txe2x80x83xe2x80x83(I)
wherein:
Cxe2x80x2 is a camptothecin group of formula II: 
xe2x80x83wherein:
R1 is selected from the group consisting of H, alkyl, aldehyde, carbonyl, alkoxy, alkylaryl, hydroxyalkyl, haloalkyl, aminoalkyl, dialkylamino, dialkylaminoalkyl, cycloaminoalkyl, aryl, aryloxy, C-glycal, nitro, cyano and O-glycosyl;
R2, R3, R4 and R5 are each independently selected from the group consisting of H, amino, hydroxy, alkyl, alkoxy, alkylthiol, alkylamino, aminoalkyl, di(alkyl)amino, cycloaminoalkyl, aminoalkoxy, aryl, aryloxy, C-glycal, cyano, methylenedioxy, formyl, nitro, halo, azido, amido, hydrazino, any of the twenty standard amino acids bonded to the A ring via the amino-nitogen atom, SR8, NR8R8, or O-glycosyl; or R3 and R4 together form a 5- or 6-member aromatic or dioxolane ring; and wherein R2 and R3, R3 and R4, or R4 and R5 taken together;
Subject to the proviso that one of R1, R2, R3, R4 and R5 is a covalent bond to L;
R6 is H, halo, alkyl, alkoxy, alkylaryl, hydroxyalkyl, or haloalkyl;
R7 is alkyl, alkylaryl, hydroxyalkyl, or aryl;
R8 is independently selected from the group consisting of H, alkyl, alkylaryl, hydroxyalkyl, aminoalkyl, acyl, or aryl;
L is a linking moiety;
T is a taxoid group, of formula III: 
xe2x80x83wherein
R11 is selected from the group consisting of H, alkyl, alkoxy, aminoalkyl and acyl;
R12 and R13 are each independently selected from the group consisting of H, alkyl, aryl, alkoxy, alkylaryl, hydroxyalkyl, haloalkyl, aminoalkyl, dialkylamino, dialkylaminoalkyl, cycloaminoalkyl, aryloxy, nitro, cyano, and halo; or a pharmaceutically acceptable salt thereof.
According to other embodiments of the present invention, the present invention relates to a pharmaceutical formulation comprising a compound according to Formula I above in a pharmaceutically acceptable carrier.
According to still other embodiments of the present invention, the present invention relates to a method of treating cancer, comprising administering to a subject in need thereof a treatment effective amount of a compound according to Formula I above. Examples of cancers that may be treated include, but are not limited to, small cell lung cancer, testicular cancer, lymphoma, leukemia, esophageal cancer, stomach cancer, colon cancer, breast cancer, ovarian cancer, central nervous system cancer, liver cancer and prostate cancer.
According to yet other embodiments of the present invention, the present invention relates to a method of inducing cellular differentiation, the method comprising contacting (in vivo or in vitro) a cancer cell with a differentiation effective amount of a compound according to formula I above.
According to other embodiments of the present invention, the present invention relates to a method of inhibiting cellular mitosis, the method comprising contacting (in vivo or in vitro) a cell with a mitosis inhibiting amount of a compound according to formula I above.